Traumatic brain injuries (TBI) are an area of significant unmet need with no approved therapeutics and a national burden of ~$77 billion annually. Astrocyte Pharmaceuticals is developing a small molecule pharmaceutical agent that would be administered by intravenous injection by emergency responders or a medical professional within 24 hours of injury to limit neuronal damage and cell death. The proprietary approach at Astrocyte Pharmaceuticals differs significantly from historical neuroprotective attempts in that it focuses on a non-neuronal cell type, the astrocyte, which has only recently received broader attention as an important cellular target for successful therapeutic research. Molecular activation of astrocytes enhances multiple healing mechanisms including protection against edema, glutamate excitotoxicity and oxidative stress. Preliminary data demonstrate significant neuroprotective benefits of these molecules in mouse models when administered within 30 minutes, 3 hours and even at 24 hours post-injury. The goal of this STTR Phase I project is to establish the ability of these small molecules to significantly enhance the inherent neuroprotective activity of astrocytes in both small and large animal TBI models. The project aims to optimize the treatment protocol (dosing, timing and frequency) that maximizes the in vitro neuronal viability benefits of ~6 candidate molecules, utilize an in vivo mouse TBI model to select a lead candidate that maximizes reduction in the magnitude and duration of whole brain edema and reactive gliosis biomarkers, and validate that the efficacy of the lead candidate in a study with a toddler piglet TBI model.